Abstract There is consistent and convincing evidence that self-reported allergies are associated with reduced risk of pancreatic cancer. Very little is understood about this association; a major limitation is the absence of studies of biomarkers of allergic response and their relation to risk. Individuals with allergy have higher levels of serum IgE, both total IgE and allergen-specific IgE. Study of these biomarkers can potentially provide a better indicator of risk than self-report, as well as provide a better understanding of the biologic processes behind this association. The specific aim of this study is to measure pre-diagnostic serum IgE -- total IgE and specific IgE to respiratory allergens and food allergens -- and their associations with risk pancreatic cancer. We hypothesize that higher levels of IgE are associated with reduced risk. We will use a nested case-control design within the Prostate, Lung, Colorectal, and Ovarian (PLCO) Screening Trial. IgE will be measured in 230 pancreatic cancer cases and 460 controls from this cohort, with 2 controls for each case individually matched on age at baseline, gender, race, and date of blood draw. In data analysis, we will investigate the association of each IgE measure with risk of pancreatic cancer, using conditional logistic regression to obtain odds ratios and to adjust for possible confounders. Because of the widespread systemic effects of pancreatic cancer, a prospective design is far stronger than a case-control design in which disease may affect IgE levels. Our study team consists of epidemiologists and a biostatistician who are experienced in pancreatic cancer research, the PLCO cohort, and in IgE measures, and a physician with clinical and research specialties in allergy. While allergies are not a risk factor that can be modified, study of IgE will provide more complete understanding of the biologic underpinnings of the association between allergies and risk. This can help develop a risk profile to identify individuals at increased risk; in addition, understanding of the biologic basis for the observed protective association can suggest novel immune-based therapies for this deadly disease.